Reliable L-Dopa Tops for Early Parkinson's

by John Gever John Gever,Deputy Managing Editor, MedPage Today
June 10, 2014

Action Points

Note that this large, randomized trial of initial Parkinson's disease therapy revealed that levodopa was more effective than dopamine agonists or MAO-B inhibitors in preserving motility scores.

Be aware that no differences in the rate of adverse events (such as dyskinesias) were seen between arms of this trial.

A large clinical trial gave a small edge to levodopa over dopamine agonists and monoamine oxidase B (MAO-B) inhibitors as initial therapy in Parkinson's disease, researchers said.

With a median of 3 years of follow-up, patients randomized to levodopa showed significantly better mobility scores than those assigned to the other two drug classes (mean difference 1.8 points, 95% CI 0.5-3.0, on the patient-rated 39-item Parkinson's Disease Questionnaire), according to Richard Gray, MA, MSc, of the University of Oxford in England, and colleagues.

Switching from the assigned treatment to another therapy because of adverse effects was also substantially less common in the levodopa group -- more than 20% of those assigned to dopamine agonists or MAO-B inhibitors stopped those agents, compared with just 2% of those initiating levodopa (P<0.0001), the researchers reported online in The Lancet.

Overall, they characterized the advantage for levodopa as "unquestionably small" but clinically significant nonetheless, since it casts doubt on previous studies suggesting that motor complications and dyskinesias are more common with levodopa than with the other drug types in long-term use.

Instead, the current study -- dubbed PD MED -- "showed no indication of any cumulative adverse effect of levodopa therapy, with no loss of benefit with time."

In an accompanying editorial, two Canadian researchers agreed that the study had adequately demonstrated that levodopa is appropriate initial therapy for most Parkinson's disease patients, but questioned the extent to which it would change current practice.

"It is now generally acknowledged that a delay or reduction in incidence of dyskinesias through initiation of dopamine agonists as opposed to levodopa in the early years, when these are generally mild and not disabling, does not necessarily translate into a better outcome in the long term when patients are typically on levodopa combined with other drugs (independent of how treatment was initiated)," they wrote.

They added that reports of impulse control disorders with dopamine agonists also began appearing after the trial began. Consequently, belief in the superiority of levodopa-sparing therapy may not be as strong as it may have been when PD MED was conceived, and levodopa may already be the preferred initial drug in the eyes of most clinicians.

"We look forward to validated surveys of prescribing practices to learn whether the results of PD MED will be practice-changing or simply practice-validating," Lang and Marras wrote.

Marian Evatt, MD, MS, a neurologist at Emory University in Atlanta, told MedPage Today much the same thing.

"I don't think it will change practice that dramatically," she said, noting that the between-group differences in outcomes were small and that increased incidence of adverse effects with levodopa-sparing therapy is already well-known.

Study Details

Gray and colleagues enrolled 1,620 patients who either had never received drug therapy for Parkinson's disease or had been on medications for less than 6 months. More than 90% were treatment-naive.

Mean age was 71 at baseline. Mean duration of disease was 0.6 years (range 0 to 13) with just over 20% of patients at stages 2.5 or higher on the Hoehn and Yahr symptom severity scale. Mean total PDQ-39 score was about 31.

Patients were randomized to open-label treatment with levodopa, a dopamine agonist, or an MAO-B inhibitor. Treating clinicians could select any approved drug within these classes and adjust the dose as needed within the label-recommended limits.

Within the dopamine agonist class, 55% of patients received ropinirole (Requip) and 29% pramipexole (Mirapex), with the remainder scattered among six other drugs. Of those randomized to MAO-B inhibitors, oral selegiline (Anipryl) was chosen for 66%, sublingual selegiline for 11%, and rasagiline (Azilect) for 21%.

Follow-up lasted for up to 7 years, but because enrollment continued into 2009, the median was 3 years, Gray and colleagues indicated.

The primary outcome was change in the mobility subscore on the PDQ-39 instrument, a 100-point, patient-completed assessment that covers a spectrum of quality-of-life issues. Secondary outcomes included the overall PDQ-39 score; cognition as measured with the Mini-Mental State Examination; onset of dementia, dyskinesias, and other motor abnormalities; death; and hospitalization or move to institutional care.

At no single time during follow-up did the PDQ-39 mobility score differ significantly between patients assigned to levodopa and to the other two groups. However, Gray and colleagues found that the average difference across the entire follow-up period favored levodopa by 1.8 points (P=0.005).

Similarly, there was an average difference of 1.0 points in the PDQ-39 summary score in favor of levodopa (95% CI 0.3-1.7, P=0.008).

For other secondary endpoints, the investigators found nonsignificant trends favoring levodopa. They noted that the upper bounds of the 95% confidence limits precluded any possibility that levodopa was substantially worse for such outcomes.

Gray and colleagues also identified some differences between the two levodopa-sparing classes. In particular, the average PDQ-39 mobility score for those assigned to MAO-B inhibitors across follow-up was better by 1.4 points (95% CI 0.0-2.9) compared with the dopamine agonist group.

Limitations

The authors noted that the open-label design was a potential limitation, but since all patients were receiving an approved active treatment, "any such bias is probably small," they wrote. Also, the use of the patient-rated PDQ-39 could be seen as a limitation.

But Gray and colleagues suggested that these design choices were strengths as well. The investigators wanted the study to mirror actual practice as much as possible, which argues for open-label treatment. Keeping the treatments unmasked also helped in recruitment and cut the trial's costs, they suggested.

Similarly, the authors said the use of patient-reported outcomes helped "provide results that are more generalizable to typical patients and, as a result, more valuable in clinical practice."

Evatt, too, applauded the open-label design and the quality-of-life measures. But she did have one complaint about the design: the exclusive use of intention-to-treat statistical analyses, in which all patients assigned to a given treatment were analyzed together even though some had switched to some other therapy.

"As a clinician, I'm often more interested in the as-treated [population]," she told MedPage Today. "I know the statisticians love the intention-to-treat analyses, but if you look at the discontinuation rates, they weren't so high that you'd expect to introduce any kind of an issue."

The study was funded by the U.K. government. One co-author reported relationships with Abbott, Boehringer Ingelheim, GlaxoSmithKline, Orion Pharma, Novartis, Teva, and UCB. Other authors disclosed no relevant relationships with industry.

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